Frontotemporal dementia (FTD) is an age-dependent neurodegenerative condition associated with focal atrophy of the frontal and/or temporal lobes and recognized now as the most common form of dementia before the age of 60. Unfortunately, the molecular pathogenesis of FTD remains largely unknown and effective treatments are not available. Recent exciting advances indicate that FTD is often associated with amyotrophic lateral sclerosis (ALS) and several genes are involved in thepathogenesis of both ALS and FTD, including CHMP2B, TDP-43, FUS, TBK1, and C9ORF72. How these mutant proteins cause or contribute to neuronal dysfunction and neurodegeneration in ALS and FTD remains poorly defined.

A few years ago, we cloned anovel Drosophila gene called shrub, which encodes a key component of ESCRT-III and regulates dendritic morphogenesis. In cultured cortical neurons, we found that dysfunctional ESCRT-III, lacking essential components (such as mSnf7-2, one of the mouse homologs of Shrub) or containing ectopically expressed FTD3-associated mutant CHMP2B, causes dendritic retraction,autophagosome accumulation and eventual neurodegeneration. Through an unbiased genetic screen in a Drosophila modelof FTD3, we identified several genetic modifiers of CHMP2B toxicity in vivo that are currently being characterized. We have also been using Drosophila models to study other ALS/FTD genes, in paticular, C9ORF72.

We have also established patient-specific induced pluripotent stem cells (iPSC) models of FTD and ALS with mutations in progranulin, TDP-43, C9ORF72 and other genes. Over the next a few years, we will use a combination of molecular, cellular, and genetic approaches in both Drosophila and iPSCs models to further dissect the pathogenic mechanisms involving these ALS/FTD disease genes. Our ultimate goal is to identify common underlying pathogenic pathways as potential targets for therapeutic interventions in both ALS and FTD.